The study of retrovirus-induced cancers in animal models has resulted in the identification of scores of genes involved in virtually all aspects of cell growth and regulation. It is well-established that MMTV, a murine retrovirus that causes breast cancer in mice, integrates next to a number of cellular oncogenes in tumor cells, thereby inducing their inappropriate expression. However, we have recently found that ectopic expression of the MMTV envelope protein in normal mammary epithelial cells results in their phenotypic transformation and that an immuno-tyrosine based activation motif (ITAM) in this protein is critical to this activity. ITAMs are commonly found in receptors expressed in hematopoietic cells and are negatively regulated by cell-type specific modulators such as the B-cell specific molecule CD22. We speculate that uncontrolled signaling by the envelope protein in an epithelial cell, which lacks such modulators, is an early step in the MMTV transformation process. ITAM-mediated signaling may be required for virus infection in vivo and the induction of dysregulated cell growth may be a by-product of this requirement. Because ITAMs are found both in viral and cellular proteins, inappropriate expression of such signaling molecules represents a novel mechanism of transformation. Thus, the overall goals of this proposal are to determine the in vivo role of the MMTV envelope protein in mammary gland infection and tumorigenesis and thereby to determine whether ITAM-containing proteins play a role in breast and other non-hematopoietic cancers. These studies are of potential importance in developing new treatment paradigms for breast and other cancers, especially those associated with viruses that encode proteins that activate ITAM-mediated signaling.